The E3 ubiquitin ligase HECTD3 controls immune colonic inflammation by restricting Myd88 activation and signaling

Ubiquitination is an important post-translational modification associated with essential cellular processes and implicated in regulation of immunity. Here we show that deletion of the E3 ubiquitin ligase Hectd3, germline or in hematopoietic compartment, including in CD11c + cells, causes a more severe DSS-induced colitis and increased production of proinflammatory cytokines. Hectd3 mRNA levels were found reduced in colonic tissues of patients with ulcerative colitis (UC), which highlights a potential role for Hectd3 in regulating inflammatory responses in UC. We identified Myd88, a central adaptor in the TLR/IL1R signaling and inflammatory response, as a target for Hectd3 ubiquitination. We demonstrate that Hectd3 directly ubiquitinates Myd88 through K27-linked Poly-Ub chains in a nondegradative manner. Hectd3 KO GM-CSF-bone marrow derived cells treated with the TLR4 ligand lipopolysaccharide (LPS) produced more proinflammatory cytokines, show elevated phosphorylation of NF-κB and IRAK4, as well as elevated association of Myd88 with IRAK4, demonstrating that Hectd3 controls Myd88-IRAK4-NF-κB axis. Inhibition of Myd88 activity rescued colitis severity in the Hectd3 KO mice, including the elevated proinflammatory cytokine production. Thus, our results establish Myd88 as a new target for Hectd3 non-degradative polyubiquitination and restriction of immune colonic inflammation.

Authors

Institutions

Publication Details

Journal
JCI Insight
Published
2026-09-24
DOI
https://doi.org/10.1172/jci.insight.185437
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
article

The E3 ubiquitin ligase HECTD3 controls immune colonic inflammation by restricting Myd88 activation and signaling

Dorina Avram, Mariola J. Ferraro, Olga A. Guryanova, Ross Tomaino et al.
JCI Insight
Ubiquitin and proteasome pathways
article

The E3 ubiquitin ligase HECTD3 controls immune colonic inflammation by restricting Myd88 activation and signaling

Dorina Avram, Mariola J. Ferraro, Olga A. Guryanova, Ross Tomaino, Martina Molgora, Timothy I. Shaw, Zheng Ruan, Amer A. Beg, Paulo C. Rodrı́guez, Shamima Islam, Alexander J. Kwiatkowski, Upasana Parthasarathy, Christian Jobin, Τόμας Ζελένκα, Shahnewaj Mannan, Raghwendra Pratap Singh, Sayan Chakraborty, Leonardo Silvane, Lixin Wan, Hongmin Li, Sang Yong Kim, Amreen Naveen, Divya Priyanka Talada, Michael G.M. Grant, Valeriu B. Cismasiu, Theodore Drashansky, Jonathan J. Cho, Sephra Chyanne Vickers, Benjamin G. Keselowsky, Xintong Liu, Ashley Zuniga
article en

Abstract

Ubiquitination is an important post-translational modification associated with essential cellular processes and implicated in regulation of immunity. Here we show that deletion of the E3 ubiquitin ligase Hectd3, germline or in hematopoietic compartment, including in CD11c + cells, causes a more severe DSS-induced colitis and increased production of proinflammatory cytokines. Hectd3 mRNA levels were found reduced in colonic tissues of patients with ulcerative colitis (UC), which highlights a potential role for Hectd3 in regulating inflammatory responses in UC. We identified Myd88, a central adaptor in the TLR/IL1R signaling and inflammatory response, as a target for Hectd3 ubiquitination. We demonstrate that Hectd3 directly ubiquitinates Myd88 through K27-linked Poly-Ub chains in a nondegradative manner. Hectd3 KO GM-CSF-bone marrow derived cells treated with the TLR4 ligand lipopolysaccharide (LPS) produced more proinflammatory cytokines, show elevated phosphorylation of NF-κB and IRAK4, as well as elevated association of Myd88 with IRAK4, demonstrating that Hectd3 controls Myd88-IRAK4-NF-κB axis. Inhibition of Myd88 activity rescued colitis severity in the Hectd3 KO mice, including the elevated proinflammatory cytokine production. Thus, our results establish Myd88 as a new target for Hectd3 non-degradative polyubiquitination and restriction of immune colonic inflammation.

JCI Insight
University of Arizona (US), Thomas Jefferson University (US), Moffitt Cancer Center (US), University of Florida (US), Jefferson Institute (US), New York University (US), Florida College (US)
Good health and well-being
Openalex Percentile: Top 19%
Ubiquitin and proteasome pathways
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.